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研究揭示产生吗啡耐受性的分子机制

研究揭示吗啡耐受性的分子机制

现如今,疼痛已被贴上了隐形健康危机的标签,对人类的生活质量有着极大的负面影响,并且是最常见的致残原因。

一个国际研究小组现已发现,脊髓中的小神经胶质细胞是吗啡引起的痛觉过敏的罪魁祸首,这将有助于开发出缓解疼痛的新方法。吗啡耐受性是指,当使用吗啡来减轻疼痛的作用不明显时,往往需要增加剂量,但这同时会造成病人对吗啡的耐受性,导致吗啡加量而疼痛却加剧的“矛盾”现象。相关论文发表在《自然·神经科学》(Nature Neuroscience)网络版上。

研究人员表示,当吗啡作用于小神经胶质细胞中的某些受体时,引发了一连串的反应,最终增加了负责传递疼痛的神经细胞的活性。研究人员确定了负责吗啡的这种副作用的分子:蛋白质KCC2。吗啡抑制了这种蛋白质的活性,引起异常的疼痛感知。通过恢复KCC2的正常活动,我们有可能阻止痛觉过敏。研究人员正在测试能够维持KCC2功能的新分子,以防止吗啡引起的痛觉过敏。

这项研究发现可能对那些患有癌症或神经损伤等各类顽固性疼痛的患者,以及因痛觉过敏已停止服用吗啡或其他阿片类药物的人有重大影响。

了解更多:

Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis

Nature Neuroscience, 06 January 2013 | doi:10.1038/nn.3295

Received 08 October 2012 Accepted 05 December 2012 Published onlineA major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K+-Cl− co-transporter KCC2, impairing Cl−homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor–dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.

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